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Spatially-defined macrocycles incorporating peptide bond surrogates

a macrocyclic compound and peptide technology, applied in the direction of peptide/protein ingredients, drug compositions, metabolic disorders, etc., can solve the problems of long experimentation and long time required to control the conformation within a single cyclic molecule, and the usual limitations of direct use of peptides in new materials,

Active Publication Date: 2009-06-23
OCERA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to the use of peptide bond surrogates in the context of conformationally-defined cyclic molecules. The invention provides compounds of formula (I) which incorporate peptide bond surrogates. The compounds have a unique structure and can be used in various applications such as drug discovery and material science. The technical effect of the invention is the creation of new compounds with improved properties and functions.

Problems solved by technology

However, these novel materials are still plagued by the usual limitations associated with the direct use of peptides as pharmaceuticals, although many are used in human and veterinary medicine due to their potency and selectivity.
Although peptides are highly potent and selective biological agents, their use as pharmaceutical products is limited byPoor aqueous solubilityMetabolic instability, particularly to proteasesLow oral bioavailabilityInadequate membrane permeabilityDifficulty in transport to site of action in tissues and organsPotential antigenicityShort pharmacokinetic half-life decreases duration of pharmacological actionSide effects due to the presence of receptors for the peptide in other non-target areas of an organismHigh manufacturing costs
However, the ability to control conformation within a single cyclic molecule often requires long experimentation in order to access the desired structure.
However, to date, no method has been described to combine the use of such tether elements with peptide bond surrogates.
However, this approach provides a constraint with the only control being provided by the length of the backbone chain employed.
This does not permit access to all the conformations that might be require in order to optimally interact within a biological system.
Until recently, the number of reports of the use of macrocyclic peptidomimetics in drug discovery has rather been limited.
However, in most of these cases, the formation of the cyclic structure was simply one step in a lengthy optimization process.
However, this moiety is not isosteric to the amide as it contains an extra atom, so that incorporation leads to larger-sized structures.
However, often this is done, not in a predictable manner, but rather determined after the construction of the molecule.
Further, to date, peptide bond surrogates have not been widely investigated in the context of cyclic structures nor in libraries, likely due to the challenges involved in their syntheses.

Method used

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  • Spatially-defined macrocycles incorporating peptide bond surrogates
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  • Spatially-defined macrocycles incorporating peptide bond surrogates

Examples

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example 1

Representative Synthesis of Macrocyclic Compound of Formula I containing Peptide Surrogate S6

[0160]The synthetic scheme is presented as FIG. 4(a). Starting from polystyrene trityl resin containing the linker shown (1-0), initial standard Fmoc deprotection of the linker furnished 1-1. This was then coupled with Fmoc Nva-OH under standard conditions. Loading of the resin based upon quantitative analysis of a cleaved aliquot at this stage was 62%. After Fmoc cleavage using standard conditions followed by coupling with Fmoc-(D)Val-OH under standard condition, 1-2 was obtained. After Fmoc group deprotection, reductive alkylation with Fmoc-(D)Tyr(OtBu)-CHO 1-3 was carried out as described in Step 1-d.

Step 1-d: Reductive Amination for Introduction of First Building Block

[0161]The following stock solutions were prepared first.[0162]Solution A: 100 mL of 1% AcOH in TMOF (trimethylorthoformate).[0163]Solution B: 100 mL of 1% AcOH in DMF / TMOF / MeOH (1:1:1).

After deprotection of the Fmoc group o...

example 2

Representative Synthesis of Macrocyclic Compound of Formula I Containing Peptide Surrogate S6

[0171]The synthetic scheme is presented as FIG. 4(b). Anchoring of Fmoc-Nva-OH as well as subsequent Fmoc deprotection were performed following standard procedures. The aldehyde 2-2 from Fmoc-(D)Val-OH was prepared in 62% yield using standard methods. Reductive amination was performed as in step 1-d. Cbz protection of the resulting product under the conditions described in step 1-e (repeated 2×) furnished the desired product 2-3.

[0172]Fmoc deprotection, coupling with Bts-(D)Tyr(OtBu)-OH, and Mitsunobu reaction of the resin bound tripeptides surrogate with 2-4 were all carried out under standard conditions to give 2-5. Macrocyclization via RCM with Hoveyda-Grubbs catalyst following the standard procedure furnished the desired product, 2-6. CLND yield: 16.1 mg. Standard deprotection of the Bts group is preferentially performed prior to deprotection of the Cbz group, with simultaneous reduction...

example 4

Representative Synthesis of Macrocyclic Compound of Formula I containing Peptide Surrogate S3

[0185]This synthesis is presented in FIG. 6. The protocol highlights an alternative method to those previously reported for introduction of the peptoid moiety.

[0186]Step 4-a: In a 500 mL solid phase synthesis reactor was suspended 2-chlorotrityl chloride resin (16.5 g, loading 2.0 mmol / g) in DCM (350 mL). The resulting slurry was agitated for 30 min, filtered and washed with DCM (2×350 mL). Separately, a solution of Bts-Gly-OH (13.4 g, 1.5 eq) and DIPEA (17.2 mL, 3.0 eq) in DCM (350 mL) was prepared to form the Bts-Gly salt. This solution of the carboxylate salt was added to the resin mixture and agitated for an additional 2.5 h. The reaction mixture was filtered and the collected resin washed successively with DMF (3×350 mL), 2-propanol (3×350 mL) and DCM (3×350 mL). Finally, any remaining active sites on the resin were neutralized by treatment with a solution of 85 / 10 / 5 DCM / MeOH / DIPEA (350...

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Abstract

Novel spatially-defined macrocyclic compounds incorporating peptide bond surrogates are disclosed. Libraries of these macrocycles are then used to select one or more macrocycle species that exhibit a specific interaction with a particular biological target. In particular, compounds according to the invention are disclosed as agonists or antagonists of a mammalian motilin receptor and a mammalian ghrelin receptor.

Description

FIELD OF THE INVENTION[0001]This invention relates to spatially-defined macrocyclic compounds incorporating peptide bond surrogates. It also relates to the generation of libraries of these macrocycles. These libraries are then used to select one or more macrocycle species that exhibit a specific interaction with a particular biological target.BACKGROUND OF THE INVENTION[0002]Peptides have been at the forefront of combinatorial chemistry technology development due to their ease of synthesis on solid support, the reproducible and high-yielding reactions involved, and the ready availability of starting materials. Peptides are the endogenous ligands for a number of enzymes and receptors. Modifications of these peptides can be performed to develop even more potent agonists or inhibitors of these same receptors and enzymes. In addition, combinatorial peptide libraries have been used to find a number of previously unknown active sequences for a wide array of enzyme and receptor systems. Ho...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K38/12C07K5/12C07D491/02C07K1/04C07K5/00C07K5/08
CPCC07K1/047C07K5/0802A61P1/00A61P1/14A61P3/00A61P3/04A61P43/00A61P5/10
Inventor DESLONGCHAMPS, PIERREDORY, YVESOUELLET, LUCVILLENEUVE, GÉRALDRAMASESHAN, MAHESHFORTIN, DANIELPETERSON, MARK L.HOVEYDA, HAMID R.BEAUBIEN, SYLVIEMARSAULT, ÉRICFRASER, GRAEME L.
Owner OCERA THERAPEUTICS INC
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